索法酮的合成

第22卷第6期沈陽(yáng)藥科大學(xué)學(xué)報Vol.22No.62005年11月Journal of Shenyang Pharmaceutical UniversityNov.2005 p.417文章編號: 1006 -2858( 2005 )06 -0417. 03索法酮的合成王紹杰,鄭洪偉,趙存良，陳欣(沈陽(yáng)藥科大學(xué)制藥工程學(xué)院,遼寧沈陽(yáng)110016)摘要:目的研究抗潰瘍藥索法酮( I )的合成工藝。方法以2’A'-二羥基苯乙酮為原料經(jīng)兩步烴化反應得中間體[2-乙?；?5<(3-甲基-2-丁烯基)氧基]苯氧基乙酸乙酯( II );對羥基苯甲醛與溴代異戊烯反應得4(3-甲基-2-丁烯基)氧基苯甲醛( II )( II )與( I )縮合得到了目標化合物。結果以2' A'-二羥基苯乙酮計三步反應總收率為44.4% ,目 標化合物結構經(jīng)核磁共振氫譜、質(zhì)譜確證。結論該法原料易得、操作簡(jiǎn)便、反應條件溫和，有-定的工業(yè)生產(chǎn)應用價(jià)值。關(guān)鍵詞: 索法酮;抗潰瘍作用;藥物合成中圖分類(lèi)號:R914文獻標識碼: A索法酮sofalcone )化學(xué)名為[5(3-甲基-2- 丁抑制作用,并能抑制菌體對胃黏膜的黏附。因此,烯基氧基-2-[3[4 (3-甲基-2-丁烯基)氧基]苯本品具有較好的臨床應用價(jià)值12]。文獻[ 3 ]報基-1-氧代-2-丙烯基苯氧基]乙酸，為一種胃黏膜道了索法酮的合成方法:以對羥基苯甲醛為原料,保護劑和組織修復劑，可用于胃潰瘍、急慢性胃炎通過(guò)與溴代異戊烯烴化得到4-(3-甲基-2-丁烯的治療,由日本大正制藥公司研制開(kāi)發(fā),1984 年基)氧基苯甲醛再以2' A-二羥基苯乙酮為原料,3月在日本上市。本品通過(guò)擴張胃黏膜血管,增分別與溴代異戊烯和溴乙酸乙酯烴化合成[ 2-乙加胃黏膜血流量和胃組織耗氧量,抑制前列腺素?；?5(3-甲基-2-丁烯基)氧基]苯氧基乙酸乙分解酶從而增加胃內前列腺素含量等藥理作用,酯二者縮合得到目標產(chǎn)物總收率為41.2%。作發(fā)揮出較強的抗潰瘍、胃黏膜保護和促進(jìn)胃黏膜者采用此路線(xiàn),并對合成工藝進(jìn)行改進(jìn)得到索法修復作用。另外,本品對幽門(mén)螺旋桿菌有較強的酮總收率為44.4%合成路線(xiàn)見(jiàn)圖1。COCH30HOCHCOOC2HsK2CO3 , acetoneBrCH2COOC2Hs，KOH+ BrCH2CH=C(CH)2acetone .OHOCHCH=C(CH)2.OCH2CH=C(CH)2IICHO+ BrCH2CH=C(CH)2 KxCO3, actoKOH, ethanol6CH2CH=C(CH)2IIICOCH=CH-O-0CH2CH=C(CH)2HO0OCH2CO中國煤化工》MHCNMHGFig.1 The synthetic route of the target compound收稿日期2005-02-28作者簡(jiǎn)仿數綱( 1968- )男(漢族)遼寧大連人副教授主要從事新藥設計與研究開(kāi)發(fā),Tel. 024-23986421 ,E-mailsjwang-99 @ yahoo . com. cn。418沈陽(yáng)藥科大學(xué)學(xué)報第22卷鹽酸調至pH=1用乙醚( 20 mLx3 )萃取,水洗有1儀器與材料機層將乙醚蒸干,所得固體用無(wú)水乙醇重結晶。熔點(diǎn)測定毛細管(自制),ARX-300核磁共振得到黃色固體11.06 g ,收率為75.2% ,mp 142~儀(美國B(niǎo)ruker 公司),1100四極桿液相色譜-質(zhì)146 C(文獻[3 ]:收率74% )。'H-NMR( CDC]3 )δ :譜聯(lián)用儀(美國Agilent 公司)。1.73(d 6H,一OCH2CH=C ( CH3 )λ1.84(d ,6H ,溴代異戊烯和2' A-二羥基苯乙酮(工業(yè)級市-OCH2CH=C(CH3))4.57(t，4H，售)其他試劑分析純,市售)。OCH2CH=dCH3) x 2 ) 4.79 ( s, 2H,-0CH2C0OH入5.48( m 2H ,- 0CH2CH- =CCH3) x2方法與結果2)6.55(d ,1H , - COCH=CH入6.67( dd ,1H ,2.1 4(3-甲基2-丁烯基)氧基苯甲醛的合成ArH入6.94(d,2H，ArH)7.24(d,1H,將10 g(0.040 mol )對羥基苯甲醛和13.2 g-COCH=CH ) 7.58( d ,2H ,ArH ) 7.73(d ,H ,(0.048 mol )無(wú)水碳酸鉀溶于10 mL丙酮中，室 溫ArH)7.78(d,H ,ArH)。MS m/z :451[M+ H]+。下攪拌30 min后滴入11 g(0.037 mol )溴代異戊烯攪拌5h。抽濾,減壓蒸出丙酮加入50 mL乙3討論酸乙酯,用質(zhì)量分數為10%的氫氧化鉀溶液洗滌，文獻3在合成4-(3-甲基-2-丁烯基)氧基苯水洗乙酸乙酯層，無(wú)水硫酸鈉干燥過(guò)夜。過(guò)濾,減甲醛時(shí)對羥基苯甲醛與溴代異戊烯等摩爾反應,壓蒸出乙酸乙酯,得到淡紅色液體5.6 g ,收率為反應結束后減壓蒸出產(chǎn)品。作者通過(guò)改變反應物80%(文獻[3]:bp 92~94 C/6.75x 10-3Pa ,收率配比使對羥基苯甲醛稍過(guò)量反應結束后用質(zhì)量84% )分數為10%的氫氧化鉀水溶液洗滌將過(guò)量的對羥2.22- 羥基4'-3甲基丁烯基-氧基苯乙酮的合成基苯甲醛成鹽洗去,不需減壓蒸餾即可得到純品。將10g0.066 mol )2' A4-二羥基苯乙酮和11 g合成24羥基-4(3-甲基-丁烯基)氧基苯乙酮時(shí)(0.080mol)無(wú)水碳酸鉀溶于120mL干燥的丙酮文獻3采用將反應物-次性加入到反應瓶中進(jìn)行中室溫下攪拌0.5h后滴入13 g0.088 mol )溴代反應的方法,反應結束后用乙醚、石油醚的混合溶異戊烯25~30 C攪拌3h蒸干丙酮放冷得到Q劑重結晶得到純品。由于合成2-羥基- 4(3-甲基淡紅色固體用石油醚洗滌得到淡粉色固體10.34.丁烯基氧基苯乙酮時(shí)先生成鉀鹽作者采用先使g收率為71.2% mp 46.47 C ,可直接進(jìn)行下步反應2'A'二羥基苯乙酮生成鉀鹽再滴入溴代異戊烯的方(文獻3]mp 46.47 C收率76% )法此操作可使反應充分進(jìn)行無(wú)需重結晶直接進(jìn)行2.3 [2-乙?；?-(3-甲基-2-丁烯基)氧基苯氧下步反應。合成2-乙?；?(3-甲基- 2-丁烯基)基乙酸乙酯的合成氧基苯氧基乙酸乙酯時(shí),文獻[3]也采用將反應將10g0.045 mol )2'羥基-4'(3-甲基-丁烯物一次性加入到反應瓶中進(jìn)行反應的方法,反應基)氧基苯乙酮和3.05 ( 0.055 mol )氫氧化鉀溶結束后用石油醚重結晶得到純品。作者采用先使于67 mL干燥丙酮中攪拌20 min滴入8 g( 0.0482-羥基-4(3-甲基-丁烯基)氧基苯乙酮生成鉀鹽mol)溴乙酸乙酯室溫攪拌3h,抽濾減壓蒸出丙再滴入溴乙酸乙酯的方法,反應結束后用石油醚酮放冷得淺紅色晶體。用石油醚洗滌所得晶體，洗滌即得純品。通過(guò)以上改進(jìn)可使操作簡(jiǎn)化、收干燥得白色固體11.53 g收率為82.9% ,mp 63、率提高到44.4%，更適于工業(yè)化生產(chǎn)。64 C( 文獻3]imp63、64 C收率68.3% )參考文獻:2.4索法酮的合 成取14g氫氧化鉀配成質(zhì)量分數為50%的水.[ 11 Parmar N S Parmar s Anti-nlrer potential of flavonoid[ J ].溶液,加入到120 mL無(wú)水乙醇中,放冷備用。將中國煤化工8 4X3)343- 351.10g0.0326 mol[2-乙?；?5-(3-甲基-2-丁烯HCNMHGlcone[J].NipponRinsho,2002 60( S2 ) .704- 709.基)氧基苯氧基乙酸乙酯加入其中。室溫攪拌下[3 ] Kazuaki K , Katsuo H. Anti-ulcer efect of isoprenyl滴入6.2 60.0326 mol)4-(3-甲基-2-丁烯基)氧基flavonoids II synthesis and anti-ulcer activity of new chal-苯甲醛攪拌5 h ,減壓蒸出乙醇加水20 mL滴加cones related to sophoradin[ J ]. Chem Pharm Bull ,1979 27( 12) 2943 - 2953.第6期王紹杰等:索法酮的合成419Synthesis of sofalconeWANG Shao-jie , ZHENG Hong-wei , ZHAO Cun- liang , CHEN Xin( School of Pharmaceutical Engineering ,Shenyang Pharmaceutical University , Shernyang 110016 , China )Abstract : Objective To investigate the synthetic process for the anti-ulcer drug sofalcone(I ). Methods Startingfrom 2' A'-dihydroxyacetophenone ethy[ 2-acetyl-5{ 3-methyl-2-butenyloxy )phenoxy ]acetate( I ) was obtained via twosteps of alkylation ;4( 3-methy1-2- butenyloxy ) benzaldehyde( II ) was prepared by the reaction of 4-hydroxyben-zaldehyde with 1-bromo-3-methyl-2-butene .Thus the target compound was obtained through the condensation of II andII. Results Starting from 2' A-dihydroxyacetophenone ,the target compound was synthesized through a three-step pro-cedure in a total yield of 44.4% ,and its structure was confirmned by 'H-NMR and MS . Conclusions The processshould has certain value for industrial application with respect to its availability of the raw materials simple operatingprocedure and mild reacting condition .Key words : sofalcone ; anti-ulcer activity ; drug synthesis(上接第408頁(yè))Preparation of sustained-release poly( D ,L-lactide-co -glycolide ) microspheres (containing bupivacaineand the evaluation of drug release in vitroLIU Xiao-rui' , DING Ping-tian' , ZHANG Jin2 , JIANG Jing- jing2( 1. School of Pharmacy , Shenyang Pharmaceutical University ，Shenyang 110016，China ; 2. Department QAnaesthesia ,Second Clinical Hospital ,China Medical Universily , Shengyang 110001 , China )Abstract : Objective To prepare sustained-release poly( D ,L-lactide- co-glycolide X PLGA )microspheres containingbupivacaine and study drug release in vitro . Methods Ultraviole( UV )spectrophotomatry method was used for deter-mination of the drug loading percent and drug entrapment efficiency of PLGA microspheres containing bupivacaine .High-performance liquid chromatography method with UV detector was applied to detect drug release of the prepara-tion in vitro . The orthogonal design was used to optimize the preparation technology of the microspheres . The micro-spheres containing bupivacaine were prepared by the emulsification-solvent evaporation method using PLGA as carri-ers and their release characteristics were measured in vitro . Results The analytical methods for determination of thedrug loading percent ,drug entrapment efficiency and drug release of microspheres in vitro were proved to be sensi-tive ,precise and reliable. PLGA microspheres containing bupivacaine were globular and had porous surface likehoneycomb" .The yield of microspheres with diameter between 50- 100 pμm was more than 80% . The in vitro re-lease profiles could be expressed by Ritger- Peppas equation with t1/2 = 242.05 h. Conclusions The emulsification-solvent evaporation method is applicable for the preparation of PLGA microspheres containing bupivacaine.It is .shown that the microspheres containing bupivacaine have good appearance and significant in vitro sustained- releasecharacteristics. .中國煤化工Key words : bupivacaine ; microspheres ; poly( D ,L-lactide-ccYHCNMHGrvitro